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THDP17 decreases ammonia production through glutaminase inhibition. A new drug for hepatic encephalopathy therapy.

ABSTRACT: Ammonia production is implicated in the pathogenesis of hepatic encephalopathy (HE), being intestinal glutaminase activity the main source for ammonia. Management of ammonia formation can be effective in HE treatment by lowering intestinal ammonia production. The use of glutaminase inhibitors represents one way to achieve this goal. In this work, we have performed a search for specific inhibitors that could decrease glutaminase activity by screening two different groups of compounds: i) a group integrated by a diverse, highly pure small molecule compounds derived from thiourea ranging from 200 to 800 Daltons; and ii) a group integrated by commonly use compounds in the treatment of HE. Results shown that THDP-17 (10 µM), a thiourea derivate product, could inhibit the intestinal glutaminase activity (57.4±6.7%). Inhibitory effect was tissue dependent, ranging from 40±5.5% to 80±7.8% in an uncompetitive manner, showing Vmax and Km values of 384.62 µmol min(-1), 13.62 mM with THDP-17 10 µM, respectively. This compound also decreased the glutaminase activity in Caco-2 cell cultures, showing a reduction of ammonia and glutamate production, compared to control cultures. Therefore, the THDP-17 compound could be a good candidate for HE management, by lowering ammonia production.

SUBMITTER: Diaz-Herrero MM

PROVIDER: S-EPMC4201470 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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THDP17 decreases ammonia production through glutaminase inhibition. A new drug for hepatic encephalopathy therapy.

Díaz-Herrero M Mar MM del Campo José A JA Carbonero-Aguilar Pilar P Vega-Pérez José M JM Iglesias-Guerra Fernando F Periñán Ignacio I Miñano Francisco J FJ Bautista Juan J Romero-Gómez Manuel M

PloS one 20141017 10

Ammonia production is implicated in the pathogenesis of hepatic encephalopathy (HE), being intestinal glutaminase activity the main source for ammonia. Management of ammonia formation can be effective in HE treatment by lowering intestinal ammonia production. The use of glutaminase inhibitors represents one way to achieve this goal. In this work, we have performed a search for specific inhibitors that could decrease glutaminase activity by screening two different groups of compounds: i) a group ...[more]

PMID: 25329718

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Project description:Cerebral edema is common in severe hepatic encephalopathy and may be life threatening. Bolus 23.4% hypertonic saline improves surveillance neuromonitoring scores, although its mechanism of action is not clearly established. We investigated the hypothesis that bolus hypertonic saline decreases cerebral edema in severe hepatic encephalopathy utilizing a quantitative technique to measure brain and cerebrospinal fluid volume changes.Retrospective analysis of serial CT scans, and clinical data for a case-control series were performed.ICUs of a tertiary care hospital.Patients with severe hepatic encephalopathy treated with 23.4% hypertonic saline and control patients who did not receive 23.4% hypertonic saline.23.4% hypertonic saline bolus administration.We used clinically obtained CT scans to measure volumes of the ventricles, intracranial cerebrospinal fluid, and brain using a previously validated semiautomated technique (Analyze Direct, Overland Park, KS). Volumes before and after 23.4% hypertonic saline were compared with Wilcoxon signed rank test. Associations among total cerebrospinal fluid volume, ventricular volume, serum sodium, and Glasgow Coma Scale scores were assessed using Spearman rank correlation test. Eleven patients with 18 administrations of 23.4% hypertonic saline met inclusion criteria. Total cerebrospinal fluid (median, 47.6?mL [35.1-69.4 mL] to 61.9?mL [47.7-87.0 mL]; p < 0.001) and ventricular volumes (median, 8.0?mL [6.9-9.5 mL] to 9.2?mL [7.8-11.9 mL]; p = 0.002) increased and Glasgow Coma Scale scores improved (median, 4 [3-6] to 7 [6-9]; p = 0.008) after 23.4% hypertonic saline. In contrast, total cerebrospinal fluid and ventricular volumes decreased in untreated control patients. Serum sodium increase was associated with increase in total cerebrospinal fluid volume (r = 0.83, p < 0.001), and change in total cerebrospinal fluid volume was associated with ventricular volume change (r = 0.86; p < 0.001).Total cerebrospinal fluid and ventricular volumes increased after 23.4% hypertonic saline, consistent with a reduction in brain tissue volume. Total cerebrospinal fluid and ventricular volume change may be useful quantitative measures to assess cerebral edema in severe hepatic encephalopathy.

Dataset Information

THDP17 decreases ammonia production through glutaminase inhibition. A new drug for hepatic encephalopathy therapy.

Publications

THDP17 decreases ammonia production through glutaminase inhibition. A new drug for hepatic encephalopathy therapy.

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